Distinctive structural requirement for the binding of uncompetitive blockers (phencyclidine-like drugs) to the NMDA receptor

Varda Nadler, Yoel Kloog, Mordechai Sokolovsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The kinetic and equilibrium binding of various tritiated phencyclidine (PCP)-like drugs to the N-methyl-D-aspartate (NMDA) receptor of rat brain cortex were analyzed and compared. The tested drugs showed the following rank order of affinity toward the receptor: [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate ([3H]MK-801) > [3H]-N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP > [3H]-N[1-(3-aminophenyl)cyclohexyl]piperidine ([3H]NH2PCP) > [3H]phencyclidine ([3H]PCP) > [3H]-N[1(3-azidophenyl)cyclohexyl]piperidine ([3H]AZ-PCP) > [3H]-N-[1-(3-nitrophenyl)cyclohexyl]piperidine ([3H]NO2PCP) (Kd = 3, 10, 24, 35, 100 and 2500 nM, respectively). All of the labeled ligands were found to associate with and dissociate from the receptor: both processes occurred at relatively slow rates in the absence of added glutamate and its allosteric effector glycine (basal binding) but were markedly accelerated upon their addition. For each drug, the basal association rate was similar to the basal dissociation rate. However, the basal rates differed markedly among the different drugs tested, and their apparent time constants characterizing the first-order process of basal ligand binding (kb) correlated inversely with their equilibrium binding constants (KD). The recorded kb values (10-3 min-1) were 2.3, 5.1, 12.4, 44 and 79 for [3H]MK-80], [3H]TCP. [3H]NH2PCP, [3H]PCP and [3H]AZ-PCP, respectively. The glutamate- and glycine-induced dissociation rates (characterized by the apparent time constant k-1) differed among the ligands and also correlated inversely with their KD values. Their induced association rates, however, were similar. The above finding as well as the significant correlation between kb, k-1 and KD, strongly suggest that the overall dissociation time constant is the major factor contributing to the differences in affinity among the ligands. Taken together, the results point to the existence within the NMDA receptor channel of a specific binding domain for PCP-like drugs, with a distinctive structural requirement for the binding of the uncompetitive blockers. It seems likely that charge transfer interactions play a major role in the binding processes which lead to the NMDA channel block produced by these ligands and to the slow rate of ligand dissociation from their sites.

Original languageEnglish
Pages (from-to)97-104
Number of pages8
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Issue number2-3
StatePublished - 13 Mar 1990


FundersFunder number
Commission of the European Communities5-ROI-DAD4168-03
National Council for Research and Development, Israel
National Institutes of Health
National Institute on Drug AbuseR01DA004168


    • Brain (rat)
    • MK-801
    • NMDA receptor
    • Phencyclidine derivatives
    • Structure-activity relationship (SAR)
    • TCP (N-[I-(2-thienyl)cyclohexyl]piperidine)


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